We hypothesize that proper retinal hydration is maintained by a balance of the bimodal functions of interferon gamma on the retinal pigment epithelium. Mounting evidence strongly suggests that the immune system plays an important role in angiogenesis. Pro-inflammatory cytokines, such as IFNg, IL-6, TNFa and IL-1b are the major cytokines in the pathogenesis of ocular inflammatory diseases and been shown to have receptors on RPE. TNFa, IL-6 and IL-1b are regarded as pro-angiogenic factors. However, IFNg is widely accepted as an anti-angiogenic cytokine due to its inhibitory effect on endothelial cell growth and capillary formation in other organ systems. We have evaluated the effect of interferon gamma on the JAK/STAT pathway, a signal transduction pathway also present in Human RPE cells. Fluid transport assays were performed to examine whether IFN induced changes in fluid transport across hfRPE monolayers. IFNg (10 ng/ml) addition to the basal bath increased JV by 8.6 ulcm-2hr-1, reflecting an increase in fluid absorption from the retinal to the choroidal side of the tissue. There were no apparent changes in cell viability as measured by transepithelial potential (TEP) and total tissue resistance (RT). In 10 experiments, the mean JV increased from 12.9 +/- 1.6 to 20.5 +/- 3.1 uL*cm-2*hr-1 (mean +/- s.e.m., P< 0.01). A previously tested in vivo rodent model of retinal detachment was used to measure the effect of INFg on re-absorption following retinal detachment. Initial detachment was created by injecting approximately 1ul of osmotically-balanced, modified phosphate-buffered saline (MPBS) solution into the sub-retinal space (SRS). Detachments that did not change in volume more than 10% in the first 30 minutes were used to test INFg effects. After detachment stabilization volume was measured by OCT imaging, INFg (40ul of 100ng/ml) was added to the anterior surface of the eye via eye drops (Celluvisc). A series of 3D OCT images were recorded at different time point. Addition of INFg to the anterior eye surface caused a significant, rapid 50% decrease in retinal detachment volume in the first hour of observation. This result is consistent with the observed fluid transport increase in RPE cells in vitro. We hypothesize that in the normal RPE cell, both pathways are functioning simultaneously to maintain the normal retinal hydration. The Jak/Stat pathway, if stimulated from basal side, will induce fluid absorption to resolve the abnormal accumulation of edema. Other regulatory targets of Jak/Stat pathway include micro RNA 155(miR-155), inflammasome, and IL-18 secretion. We also hypothesize that monotonic elevation of steady-state miR-155 levels in RPE occur with age, contributing to constitutive inflammasome activation. Modulation of IL-18 and IFNg levels may lead to therapeutic effect to reverse pathological changes associated with uveitis.